Nephrolithiasis is a common, costly and recurrent condition, but there is sparse information on the influence of genetic factors and gene-environment interactions. The overall long-term objective of this Program Project is to expand our knowledge of the physiologic processes, genetic predisposition, and gene-environment interactions that affect the overall risk of kidney stone formation in order to formulate optimal preventive strategies. Projects 1 and 2 focus on basic physiological issues in the control of renal calcium, oxalate, and citrate excretion, which are critical for calcium oxalate stone formation. Specifically, the physiological role and regulation of key oxalate and citrate transporters will be studied in Project 1. Project 2 will serve to refine our understanding of the renal physiological role of the calcium sensing receptor, which functions as a key regulatory locus for calcium, water, and salt transport all along the nephron. The spectrum of genetic variation in the genes under physiological study in Projects 1 and 2 as well as other important candidate genes will be determined with the aid of Core A, the genetics Core. Project 3 will then examine the impact of genetic variation (using genome wide association studies) and its interaction with diet on 24 hour urine composition in 3000 well-phenotyped participants with and without a history stone formation, building on the unique resources and expertise available for this project. Finally, the functional effect of non-synonymous coding SNPs will be studied in Projects 1 and 2; this will help to focus Project 3 on genetic variability with functional consequences and will also help define the physiological underpinnings of the genetic associations found in Project 3. By studying this complex disease from a variety of approaches, ranging from basic physiology to urine composition, this Program Project will greatly enhance our understanding of the pathobiology of nephrolithiasis and the findings will have direct clinical application.